New Perspectives on Rodent Models of Advanced Paternal Age: Relevance to Autism

Offspring of older fathers have an increased risk of various adverse health outcomes, including autism and schizophrenia. With respect to biological mechanisms for this association, there are many more germline cell divisions in the life history of a sperm relative to that of an oocyte. This leads to more opportunities for copy error mutations in germ cells from older fathers. Evidence also suggests that epigenetic patterning in the sperm from older men is altered. Rodent models provide an experimental platform to examine the association between paternal age and brain development. Several rodent models of advanced paternal age (APA) have been published with relevance to intermediate phenotypes related to autism. All four published APA models vary in key features creating a lack of consistency with respect to behavioral phenotypes. A consideration of common phenotypes that emerge from these APA-related mouse models may be informative in the exploration of the molecular and neurobiological correlates of APA

Influence of energy balance on the antimicrobial peptides S100A8 and S100A9 in the endometrium of the postpartum dairy cow

Uterine inflammation occurs after calving in association with extensive endometrial remodelling and bacterial contamination. If the inflammation persists, it leads to reduced fertility. Chronic endometritis is highly prevalent in high-yielding cows that experience negative energy balance (NEB) in early lactation. This study investigated the effect of NEB on the antimicrobial peptides S100A8 and S100A9 in involuting uteri collected 2 weeks post partum. Holstein-Friesian cows (six per treatment) were randomly allocated to two interventions designed to produce mild or severe NEB (MNEB and SNEB) status. Endometrial samples were examined histologically, and the presence of neutrophils, macrophages, lymphocytes and natural killer cells was confirmed using haematoxylin and eosin and immunostaining. SNEB cows had greater signs of uterine inflammation. Samples of previously gravid uterine horn were used to localise S100A8 and S100A9 by immunohistochemistry. Both S100 proteins were present in bovine endometrium with strong staining in epithelial and stromal cells and in infiltrated leucocytes. Immunostaining was significantly higher in SNEB cows along with increased numbers of segmented neutrophils. These results suggest that the metabolic changes of a post-partum cow suffering from NEB delay uterine involution and promote a chronic state of inflammation. We show that upregulation of S100A8 and S100A9 is clearly a key component of the early endometrial response to uterine infection. Further studies are warranted to link the extent of this response after calving to the likelihood of cows developing endometritis and to their subsequent fertility

The Effects of Breeding Protocol in C57BL/6J Mice on Adult Offspring Behaviour

Animal experiments have demonstrated that a wide range of prenatal exposures can impact on the behaviour of the offspring. However, there is a lack of evidence as to whether the duration of sire exposure could affect such outcomes. We compared two widely used methods for breeding offspring for behavioural studies. The first involved housing male and female C57Bl/6J mice together for a period of time (usually 10–12 days) and checking for pregnancy by the presence of a distended abdomen (Pair-housed; PH). The second involved daily introduction of female breeders to the male homecage followed by daily checks for pregnancy by the presence of vaginal plugs (Time-mated; TM). Male and female offspring were tested at 10 weeks of age on a behavioural test battery including the elevated plus-maze, hole board, light/dark emergence, forced swim test, novelty-suppressed feeding, active avoidance and extinction, tests for nociception and for prepulse inhibition (PPI) of the acoustic startle response. We found that length of sire exposure (LSE) had no significant effects on offspring behaviour, suggesting that the two breeding protocols do not differentially affect the behavioural outcomes of interest. The absence of LSE effects on the selected variables examined does not detract from the relevance of this study. Information regarding the potential influences of breeding protocol is not only absent from the literature, but also likely to be of particular interest to researchers studying the influence of prenatal manipulations on adult behaviour

Advanced Paternal Age Is Associated with Impaired Neurocognitive Outcomes during Infancy and Childhood

Using a sample of children from the US Collaborative Perinatal Project, John McGrath and colleagues show that the offspring of older fathers exhibit subtle impairments on tests of neurocognitive ability during infancy and childhood

How Can Animal Models Inform the Understanding of Cognitive Inflexibility in Patients with Anorexia Nervosa?

Deficits in cognitive flexibility are consistently seen in patients with anorexia nervosa (AN). This type of cognitive impairment is thought to be associated with the persistence of AN because it leads to deeply ingrained patterns of thought and behaviour that are highly resistant to change. Neurobiological drivers of cognitive inflexibility have some commonalities with the abnormal brain functional outcomes described in patients with AN, including disrupted prefrontal cortical function, and dysregulated dopamine and serotonin neurotransmitter systems. The activity-based anorexia (ABA) model recapitulates the key features of AN in human patients, including rapid weight loss caused by self-starvation and hyperactivity, supporting its application in investigating the cognitive and neurobiological causes of pathological weight loss. The aim of this review is to describe the relationship between AN, neural function and cognitive flexibility in human patients, and to highlight how new techniques in behavioural neuroscience can improve the utility of animal models of AN to inform the development of novel therapeutics

Increasing paternal age alters anxiety-related behaviour in adult mice

Advanced paternal age (APA) is associated with an increased risk of adverse health outcomes in offspring, including autism and schizophrenia. In the present study, we investigated the behaviour of young (3-month-old; Control), middle aged (12 to 15-month-old; APA1) and old (24-month-old; APA2) C57BL/6J sires and their adult offspring. Male and female mice were tested at 10 weeks of age on a behavioural test battery including the elevated plus-maze, hole board, light/dark emergence, forced swim test, novelty-suppressed feeding and for prepulse inhibition of the acoustic startle response. Increasing the APA sire age to 24 months was shown to be associated with increased anxiety-related behaviour in the offspring, and indicated that increasing APA sire age produced a more robust hypoexplorative phenotype. Thus, increasing paternal age was associated with an increase in severity of an anxiogenic phenotype in their adult offspring. Ultimately, the results of these studies show that mouse models of APA are valuable for elucidating the mechanisms by which APA influences brain-related outcomes